Calcium phosphate microcrystals in the renal tubular fluid accelerate chronic kidney disease progression.

The Western pattern diet is rich not only in fat and calories but also in phosphate. The negative effects of excessive fat and calorie intake on health are widely known, but the potential harms of excessive phosphate intake are poorly recognized. Here, we show the mechanism by which dietary phosphate damages the kidney. When phosphate intake was excessive relative to the number of functioning nephrons, circulating levels of FGF23, a hormone that increases the excretion of phosphate per nephron, were increased to maintain phosphate homeostasis. FGF23 suppressed phosphate reabsorption in renal tubules and thus raised the phosphate concentration in the tubule fluid. Once it exceeded a threshold, microscopic particles containing calcium phosphate crystals appeared in the tubule lumen, which damaged tubule cells through binding to the TLR4 expressed on them. Persistent tubule damage induced interstitial fibrosis, reduced the number of nephrons, and further boosted FGF23 to trigger a deterioration spiral leading to progressive nephron loss. In humans, the progression of chronic kidney disease (CKD) ensued when serum FGF23 levels exceeded 53 pg/mL. The present study identified calcium phosphate particles in the renal tubular fluid as an effective therapeutic target to decelerate nephron loss during the course of aging and CKD progression.

Development of a Kidney Calcification Inhibitor Employing Image-Based Profiling: A Proof-of-Concept Study.

Kidney calcification increases the risk of chronic kidney disease. However, to date, renal calcium phosphate crystallization, a main initiating and driving factor of kidney calcification, has not been explored as a drug target. Pre-clinical drug development is hampered by limited knowledge on the broad range of kidney calcification disorders, characterized by a multifactorial process of disease progression. In this work, we first established an in vitro calcification profiling platform to accelerate pre-clinical drug discovery. The image-based profiling assay allowed the rapid testing of several ionic stimuli and/or inhibitory molecules. We then leveraged a previously established library of inositol hexakisphosphate analogues to identify a renal calcium phosphate inhibitor. A lead compound showed in vitro and in vivo efficacy to prevent calcium phosphate-induced kidney damage. In conclusion, this work reports a renal calcium phosphate inhibitor that could efficiently reduce kidney damage and emphasizes the utility and translational value of the in vitro calcification platform.

Calciprotein particles regulate fibroblast growth factor-23 expression in osteoblasts.

Fibroblast growth factor-23 (FGF23) is a hormone indispensable for maintaining phosphate homeostasis. In response to phosphate intake, FGF23 is secreted from osteocytes/osteoblasts and acts on the kidney to increase urinary phosphate excretion. However, the mechanism by which these cells sense phosphate intake remains elusive. Calciprotein particles are nanoparticles of calcium-phosphate precipitates bound to serum protein fetuin-A and are generated spontaneously in solution containing calcium, phosphate, and fetuin-A to be dispersed as colloids. In cultured osteoblastic cells, increase in either calcium or phosphate concentration in the medium induced FGF23 expression, which was dependent on calciprotein particle formation. When transition of calcium-phosphate precipitates from the amorphous phase to the crystalline phase was blocked by bisphosphonate, the calciprotein particle size was reduced and FGF23 expression was augmented, suggesting that small calciprotein particles containing amorphous calcium-phosphate precipitates function as a more potent FGF23 inducer than larger calciprotein particles containing crystalline calcium-phosphate precipitates. In mice, bolus phosphate administration by oral gavage transiently increased circulating calciprotein particle levels followed by a modest increase in FGF23 expression and serum FGF23 levels. However, continuous dietary phosphate load induced robust and persistent increase in circulating calciprotein particles and FGF23 levels. We confirmed by in vivo imaging that calciprotein particles injected intravenously extravasated into the bone marrow and were deposited on the inner surface of the bone, indicating that these particles have direct access to osteoblasts. Thus, we propose that osteoblasts induce FGF23 expression and secretion when they sense an increase in extracellular calciprotein particles following phosphate ingestion.

Angioleiomyoma of the cheek: a case report.

Angioleiomyoma is a form of subcutaneous vascular leiomyoma that usually occurs in the extremities. Leiomyoma of the oral cavity represents only 0.4% of soft tissue neoplasms and 0.06% of leiomyomas. Isolated cases of angioleiomyoma have been reported in the knee and lower thigh, gastrointestinal tract, genital and renal tract, and brain. Histopathologic examination by biopsy is necessary to establish a diagnosis, and immunohistochemical staining, along with conventional hematoxylin-eosin staining, is important. The differential diagnosis includes hemangioma and angiosarcoma. At present, surgical resection is the standard therapy for leiomyoma, and recurrence is extremely rare. We report a rare case of angioleiomyoma of the cheek in a 45-year-old man. The postoperative course was uneventful, without complications.